According to a number of recent studies, such as Patel M, Fine D R. Fibrogenesis in the pancreas after acinar cell injury. Scand J. Surg. 2005; 94(2):108-111 and Erkan M, Adler G, Apte M V, Bachem M G, Buchholz M, Detlefsen S, Esposito I, Friess H, Gress T M, Habisch H J, Hwang R F, Jaster R, Kleeff J, Kloppel G, Kordes C, Logsdon C D, Masamune A, Michalski C W, Oh J, Phillips P A, Pinzani M, Reiser-Erkan C, Tsukamoto H, Wilson J. Stella TUM: current consensus and discussion on pancreatic stellate cell research. Gut. 2012 February; 61(2): 172-178, it is known that pancreatic stellate cells (PSCs) play a critical role in the development of pancreatic fibrosis which is often accompanied with chronic pancreatitis (CP) and desmoplastic reaction of pancreatic cancer. Typically, PSCs localized at the periacinar region of the exocrine pancreas are quiescent under normal condition. As reported in Apte M V, Haber P S, Applegate T L, Norton I D, McCaughan G W, Korsten M A, Pirola R C, Wilson J S. Periacinar stellate shaped cells in rat pancreas: identification, isolation, and culture. Gut. 1998 July; 43(1):128-33, upon injury or inflammation, these PSCs tend to lose their fat-droplets and transform into myofibroblast-like phenotype which can be identified with the presence of α-smooth muscle actin (α-SMA or Acta2). Also reported in Apte M V, Wilson J S. Mechanisms of pancreatic fibrosis. Dig Dis. 2004; 22(3):273-9. and Yoo B M, Yeo M, Oh T Y, Choi J H, Kim W W, Kim J H, Cho S W, Kim S J, Hahm K B. Amelioration of pancreatic fibrosis in mice with defective TGF-beta signaling. Pancreas. 2005 April; 30(3):e71-9, the formation of these fibrotic stress filaments actually elicits the cascade of tissue repairing mechanisms in response to pro-fibrotic and/or pro-inflammatory mediators such as transforming growth factor-beta (TGF-β), tumor necrosis factor-alpha (TNF-α) and interleukin 1 beta (IL-1β) being generated upon tissue injury. As identified by van Laethem J L, Robberecht P, Resibois A, Deviere J. Transforming growth factor beta promotes development of fibrosis after repeated courses of acute pancreatitis in mice. Gastroenterology. 1996 February; 110(2):576-82, once the PSCs are activated, they produce massive extracellular matrix (ECM) proteins, namely fibronectin 1 (Fn1) and type I collagen (Col I-α1), for the purpose of tissue repairing as well as regeneration. In fact, properties of stellate cells in the pancreas are similar to those present in other organs such as liver, kidney and lung. Not merely limiting to the pancreas, the production and deposition of ECM in an imbalanced fashion in an organ causes scarring of the parenchyma that is replaced by connective tissues. This indeed leads to permanent morphological damages of the organ. Progressive fibrosis possibly results in anatomical anomalies, organ failure or cancer. Therefore, the abolishment of the overwhelmed tissue repairing mechanism is crucial to the treatment of fibrosis and the associated impairments of the organ. In the case of pancreatic fibrosis, the activation of PSCs plays a central tread in the synthesis, deposition, formulation and remodeling of the various ECM proteins and fibrogenic mediators. It is also known, as reported in Tang D, Wang D, Yuan Z, Xue X, Zhang Y, An Y, Chen J, Tu M, Lu Z, Wei J, Jiang K, Miao Y. Persistent activation of pancreatic stellate cells creates a microenvironment favorable for the malignant behavior of pancreatic ductal adenocarcinoma. Int J Cancer. 2013 Mar. 1; 132(5):993-1003 that by maintaining high levels of ECM proteins and other pro-inflammatory and/or pro-fibrotic factors, PSCs create desmoplasia and a hypoxic microenvironment that promotes the initiation, development, evasion of immune surveillance, invasion, metastasis and resistance to chemoradiation of pancreatic ductal adenocarcinoma (PDAC). PDAC is one of the most common malignant tumors with poor prognosis due to extremely high malignancy, low rate of eligibility for surgical resection and chemoradiation resistance. Increasing evidence indicates that the interaction between activated PSCs and PDAC cells plays an important role in the development of PDAC. Therefore, targeting the interaction between PSCs and PDAC cells, and/or by suppressing the activation of PSCs, may represent novel therapeutic approaches to advanced PDAC, especially therapies that target PSCs of the pancreatic tumor microenvironment.
TGF-β has been reported by previous in-vitro and in-vivo studies such as Hu Q, Noor M, Wong Y E, Hylands P J, Simmonds M S, Xu Q, Jiang D, Hendry B M, Xu Q. In vitro anti-fibrotic activities of herbal compounds and herbs. Nephrol Dial Transplant. 2009 October; 24(10):3033-41 and Schneider E, Schmid-Kotsas A, Zhao J, Weidenbach H, Schmid R M, Menke A, Adler G, Waltenberger J, Grünert A, Bachem M G. Identification of mediators stimulating proliferation and matrix synthesis of rat pancreatic stellate cells. Am J Physiol Cell Physiol. 2001 August; 281(2):C532-43, that it is as being one of the potent inducers to the activation of PSCs. In cultured LTC-14 cells, which is an immortalized rat PSC line established by Sparmann G et al as described in Sparmann, G, Hohenadl, C., Tornoe, J., Jaster, R., Fitzner, B., Koczan, D., Thiesen, H. J., Glass, A., Winder D., Liebe, S., and Emmrich, J. Generation and characterization of immortalized rat pancreatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2004:287, G211-219, the mRNA and protein levels of the fibrotic filament α-SMA and the production of ECM proteins namely Fn1 and Col I-α1 were remarkably elevated in response to the exogenous addition of recombinant TGF-β (5 ng/mL) in the culturing microenvironment.